Synthesis of 2-(nitromethyl)ornithine from ornithine mediated by cobalt(III)

Rac.-p-(tris(2-aminoethyl)amine-2-(nitromethyl)ornithine)cobalt(III) trichloride (2d) was obtained by a simple three-step procedure from ornithine using cobalt template chemistry. p-(Tris(2-aminoethyl)amine-ornithine)cobalt(III) trichloride (2a) was obtained from tris(2-aminoethyl)amine (tren) and (S)-ornithine in the presence of cobalt(II), which was oxidised to cobalt(III) during the reaction. Complex 2a was selectively oxidised with thionyl chloride-dimethyl formamide to p-(tris(2-aminoethyl)amine-dehydro-ornithine)cobalt(III) trichloride 2b. Complex 2c, in which reaction of thionyl chloride-dimethyl formamide has also occurred at the δ-amine of ornithine, was obtained at longer reaction times. Complex 2b reacted with nitromethane anion to give rac.-p-(tris(2-aminoethyl)amino-2-(nitromethyl)ornithine)cobalt(III) trichloride (2d). The amino acid rac.-2-(nitromethyl)ornithine (1b) was released by reducing complex 2d with aqueous ammonium sulfide. Complex 2d was expected to release 2-(nitromethyl)ornithine (1b) in hypoxic cells, where the amino acid could act as an inhibitor of ornithine decarboxylase. Preliminary data indicated that complex 2d was weakly cytotoxic in one cell type studied.     

Dopamine release and molecular modeling study of some coumarin derivatives

4-aryl-2-amino-6-(4-hydroxy-2-oxo-2H-chromen-3-yl)-pyridin-3-carbonitrile (1), 4-aryl-2-oxo-6-(4-hydroxy-2-oxo-2H-chromen-3-yl)-pyridin-3-carbonitriles (2a-2c), 3-(6-aryl-1,2,5,6- tetrahydro-2-thioxopyrimidin-4-yl)-4-hydroxy-2H-chromen-2-one (3a, 3b) and pyrazol-3-yl-4-hydroxycoumarin derivatives (4a-4c, 5, 6a, 6b, 7a, 7b, and 8a-8c) were prepared in order to measure their % change dopamine release in comparison to amphetamine as reference, using PC-12 cells in different concentrations. In addition, the molecular modeling study of the compounds into 3BHH receptor was also demonstrated. The calculated inhibition constant (k_i) implemented in the AutoDock program revealed identical correlation with the experimental results to that obtained binding free energy (ΔG_b) as both parameters revealed reasonable correlation coefficients (R²) being 0.51 involving 10 compounds; (1, 2b, 2c, 3a, 3b, 4a, 4b, 6a, and 8c).     

New insight in coordination of vic-dioximes: Bis- and tris(E,E-dioximato)Ni(II) complexes

N,N′-Bis[allylamino]glyoxime, N,N′-bis[anilino]glyoxime, and N,N′-bis[1,2,3,4-tetrahydro-5-naphthalenamino]glyoxime have been prepared from corresponding amines and (E,E)-dichloroglyoxime. These ligands gave orange-red compound with NiCl₂ in less acidic medium (pH ∼ 5) that are bis(E,E-dioximato)nickel(II) complexes {[(E,E)-Ni(HL)₂]} (1a-3a) and green compounds in acidic medium (pH ∼ 2) that are tris(E,E-dioximato)nickel(II) dichloride complexes {[(E,E)-Ni(LH₂)₃]Cl₂} (1b-3b). The crystal structures of all complexes have been determined by X-ray diffraction on a single crystal. The study of absorption spectra of these two types of complexes shows that they may be converted to each other by addition of acids (1a-3a) or bases (1b-3b) and there is no way for the amphi form.     

Ruthenium(II) carbonyl chloride complexes containing pyridine-functionalised bidentate N-heterocyclic carbenes: Synthesis, structures, and impact of the carbene ligands on catalytic activities

A series of new ruthenium(II) carbonyl chloride complexes with pyridine-functionalised N-heterocyclic carbenes [Ru(Py-NHC)(CO)₂Cl₂], [Py-NHC = 3-methyl-1-(2-pyridyl)imidazol-2-ylidene, 1 (1a and 1b); 3-methyl-1-(2-picoyl)imidazol-2-ylidene, 2 (2a and 2b); 3-methyl-1-(2-pyridyl)benzimidazolin-2-ylidene, 3 (3b); 3-methyl-1-(2-picoyl)benzimidazolin-2-ylidene, 4 (4a and 4b); 1-methyl-4-(2-pyridyl)-1,2,4-triazoline-5-ylidene, 5 (5a and 5b)] have been prepared by transmetallation from the corresponding silver carbene complexes and characterized by NMR, IR spectroscopy and elemental analysis. In these complexes with bidentate Py-NHC ligands, one CO ligand is trans to the Py ligand. In 1a, 2a, 4a, and 5a, the NHC ligand is trans to the other CO ligand, thus leaving the two Cl⁻ ligands trans to each other. In 1b, 2b, 3b, 4b, and 5b, the NHC ligands are trans to one Cl⁻ ligand, and the two Cl⁻ ligands are cis to each other. The structures for 1b, 2b, 3b and 4b have been determined by single-crystal X-ray diffraction. These complexes are efficient catalysts in the transfer hydrogenation of acetophenone and their catalytic activities are found to be influenced by electronic effect of the N-heterocyclic carbene ligands.     

Hydrogen-halide versus alkyl-halide oxidative addition in dimethyl platinum(II) complexes: Crystal structure of [PtBr2(bpy)]

Dimethyl platinum(II) complexes [PtMe₂(NN)] {NN = bu₂bpy (4,4′-di-tert-butyl-2,2′-bipyridine) (1a), bpy (2,2′-bipyridine) (1b), phen (1,10-phenanthroline) (1c)} reacted with commercial 3-bromo-1-propanol in the presence of 1,3-propylene oxide to afford cis, trans- [PtBrMe₂{(CH₂)₃OH}(NN)] (NN = bu₂bpy (2a), bpy (2b), phen (2c)). On the other hand, [PtMe₂(NN)] (1a)-(1b) reacted with the trace of HBr in commercial 3-bromo-1-propanol to give [PtBr₂(NN)] (NN = bu₂bpy (3a), bpy (3b)). The reaction pathways were monitored by ¹H NMR at various temperatures. Treatment of 1a-1b with a large excess of 3-bromo-1-propanol at −80 °C gave the corresponding methyl(hydrido)platinum(IV) complexes [PtBr(H)Me₂(NN)] (NN = bu₂bpy (4a), bpy (4b)) via the oxidative addition of dimethyl platinum(II) complexes with HBr. The complexes [PtBr(H)Me₂(NN)] decomposed by reductive elimination of methane above −20 °C for bu₂bpy and from −20 to 0 °C for bpy analogue to give methane and platinum(II) complexes [PtBrMe(NN)] (5a)-(5b) and then decomposed at about 0 °C to yield [PtBr₂(NN)] and methane. When the reactions were performed at a molar ratio of Pt:RX/1:10, the corresponding complexes [PtBrMe(NN)] (5a)-(5b) were also obtained. The crystal structure of the complex 3b shows that platinum adopts square planar geometry with a twofold axis through the platinum atom. The Pt…Pt distance (5.164 Å) is considerably larger than the interplanar spacing (3.400 Å) and there is no platinum-platinum interaction.     

Functional mimics of catechol oxidase by mononuclear copper complexes of sterically demanding [NNO] ligands

Several mononuclear copper complexes 1(a-b) and 2(a-b) supported over sterically demanding [NNO] ligands namely, N-(aryl)-2-[(pyridin-2-ylmethyl)amino]acetamide [aryl = 2,6-diethylphenyl (1) and mesityl (2)], exhibit catecholase-like activity in performing the aerial oxidation of 3,5-di-t-butylcatehol (3,5-DTBC) to 3,5-di-t-butyl-catequinone (3,5-DTBQ) under ambient conditions. The 1(a-b) and 2(a-b) complexes were directly synthesized from the reaction of the respective ligands 1-2 with CuX₂·nH₂O (X = Cl, NO₃, n = 2, 3) in 55-85% yield. Mechanistic insights on the catalytic cycle as obtained by density functional theory studies for a representative complex 1a suggest that an intramolecular hydrogen transfer, from a catechol-OH moiety to a copper bound superoxo moiety, form the rate-determining step of the oxidation process, displaying an activation barrier of 18.3 kcal/mol (ΔG^‡) [6.9 kcal/mol in Δ(PE + ZPE)^‡ scale].     

Copper (II) and cobalt (II) complexes of chiral tetrathiafulvalene-oxazoline (TTF-OX) and tetrathiafulvalene-thiomethyl-oxazoline (TTF-SMe-OX) derivatives

Synthesis and single crystal X-ray structures of the first paramagnetic transition metal complexes containing chiral ethylenedithio-tetrathiafulvalene-oxazoline (EDT-TTF-OX) 1a-c and ethylenedithio-tetrathiafulvalene-thiomethyloxazoline 2 (EDT-TTF-(SMe)OX) ligands based on copper (II) and cobalt (II) are described. The racemic [EDT-TTF-OX][Cu(hfac)₂] complex 3a crystallizes in the triclinic centrosymmetric space group , whereas the enantiopure counterparts 3b-c crystallize in the triclinic non-centrosymmetric space group P1. Cu(II) adopts a distorted square pyramidal coordination geometry, a much weaker Cu?S_TTF interaction also being identified. The same coordination pattern around Cu(II) is observed in the complex [(rac)-EDT-TTF-(SMe)OX][Cu(hfac)₂] (4) in spite of the bidentate nature of the redox active ligand. DFT theoretical calculations afforded two equilibrium configurations for a corresponding model complex, in which the metal centre establishes secondary coordination either with one S_TTF or with the SMe group. The same ligand coordinates the cobalt (II) to afford the octahedral complex [(rac)-EDT-TTF-(SMe)OX][Co(hfac)₂] (5). In all these novel complexes, the paramagnetic centres are structurally and magnetically isolated. Cyclic voltammetry measurements show the stability of the radical cation species.     

An investigation of Cu(II) and Ni(II)-catalysed hydrolysis of (di)imines

The reactions of six diimine ligands with Cu(II) and Ni(II) halide salts have been investigated. The diimine ligands were Ph₂CN(CH₂)_nNCPh₂ (n = 2 (Bz₂en, 1a), 3 (Bz₂pn, 1b), 4 (Bz₂bn, 1c)), N,N′-bis-(2-tert-butylthio-1-ylmethylenebenzene)-2,2′diamino-biphenyl (2), N,N′-bis-(2-chloro-1-ylmethylenebenzene)-1,3-diaminobenzene (3) and N,N′-bis-(2-chloro-1-ylmethylenebenzene)-1,2-ethanediamine (4). Reactions of 1a-c, 2-4 with CuCl₂·2H₂O in dry ethanol at ambient temperature led to complete or partial hydrolysis of the diimine ligands to ultimately form copper diamine complexes. The non-hydrolyzed complexes of 1b and 1c, [Cu(L)Cl₂] (L = 1b, 1c), could be isolated when the reactions were carried out at low temperatures, and the half-hydrolyzed complex [Cu(Bzpn)Cl₂] could also be identified via X-ray crystallography. Similarly, reactions of 1a or 1b with NiCl₂·6H₂O or [NiBr₂(dme)] led to rapid hydrolysis of the imines and Ni complexes containing half-hydrolyzed 1a (Bzen; [trans-[Ni(Bzen)₂Br₂]) and 1b (Bzpn; [Ni(Bzpn)Br₂] could be isolated and identified via single crystal X-ray analysis. Kinetic studies were made of the hydrolyses of 1a, 1b in THF and 2 in acetone, in the presence of Cu(II), and of 1a in acetonitrile, in the presence of Ni(II). Activation parameters were determined for the latter reaction and for the copper-catalyzed hydrolysis of 2; the relatively large negative activation entropies clearly indicate rate-determining steps of an associative nature.     

Five-coordinate zinc(II) complexes with optically active Schiff bases derived from (1R,2R)-(−)cyclohexanediamine: X-ray structure and CP MAS NMR characterization of [cyclohexylenebis(5-chlorosalicylideneiminato)zinc(II)pyridine] and [cyclohexylenebis(5-bromosalicylideneiminato)zinc(II)pyridine]

Schiff bases obtained from (1R,2R)-(−)-cyclohexanediamine and 5-chloro- (1) or 5-bromosalicylaldehyde (2) are used as ligands for Zn(II) resulting in [(1R,2R)-cyclohexylenebis(5-chlorosalicylideneiminato)]zinc(II) (1a) and (1R,2R)-[cyclohexylenebis-(5-bromosalicylideneiminato)]zinc(II) (2a). In the presence of pyridine, 1a and 2a turned out into (1R,2R)-[cyclohexylenebis(5-chlorosalicylideneiminato)pyridine]zinc(II) (1b) and (1R,2R)-[cyclohexylenebis(5-bromosalicylideneiminato)pyridine]zinc(II) (2b). Coordination sphere of Zn(II) atoms in both pyridine adducts is a slightly distorted square pyramid, with N₂O₂ chromophore units and axially bonded pyridine as it is evident from single crystal X-ray analyzes of 1b and 2b. The asymmetric unit of 1b and 2b contains two molecules of complexes. The observed distances of Zn-O in both molecules indicate the rigidity of the tetradentate ligand as a main factor influencing the geometry of coordination sphere. Obtained complexes were characterized by ¹H NMR in solution and ¹³C CP MAS NMR. NOE differential experiments revealed significant steric interactions between C(6)-H in the phenyl ring, cyclohexyl C(1)-H and imine hydrogen. Significant coordination shifts of carbons in the closest proximity to the coordination center were noted as well.     

Synthesis and electrochemical aspects of group 14 iron complexes of the type (η-C5H5)Fe(L)2ER3, L2 = (CO)2, (Ph2P)2CH2; E = C, Si, Ge, Sn

The dicarbonyl and diphosphine complexes of the type (η⁵-C₅H₅)Fe(L)₂ER₃ (L₂ = (CO)₂ (a), (Ph₂P)₂CH₂ (b); ER₃ = CH₃ (1a/b); SiMe₃ (2a/b), GeMe₃ (3a/b), SnMe₃ (4a/b)) were synthesized and studied electrochemically. Cyclic voltammetric studies on the dicarbonyl complexes 1a-4a revealed one electron irreversible oxidation processes whereas the same processes for the chelating phosphine series 1b-4b were reversible. The E_ox values found for the series 1a-4a were in the narrow range 1.3-1.5 V and in the order Si > Sn ≈ Ge > C; those for 1b-4b (involving replacement of the excellent retrodative π-accepting CO ligands by the superior σ-donor and poorer π-accepting phosphines) have much lower oxidation potentials in the sequence Sn > Si ≈ Ge > C. This latter oxidation potential pattern relates directly to the solution ³¹P NMR chemical shift data illustrating that stronger donation lowers the E_ox for the complexes; however, simple understanding of the trend must await the results of a current DFT analysis of the systems.     

Unsymmetric diruthenium complexes

The new diruthenium complexes trans-[(NH₃)₅Ru(L-L)Ru(NH₃)₄(bpy-Me)](PF₆)₅ (L-L are the bridging ligands pyrazine, 2a; 4,4′dipyridyl, 2b; and trans-1,2-bis(4-pyridyl)-ethylene, 2c; bpy-Me is N-methyl-pyridyl-pyridinium) are generated from the new complexes (L-L)Ru(NH₃)₄(bpy-Me)](PF₆)₃ (1a-c) and [(NH₃)₅Ru(H₂O)](PF₆)₂. Cyclic voltammetry on the new compounds in acetonitrile electrolyte reveals two quasi-reversible oxidation steps corresponding to the two Ru^II/III couples in 2b and 2c and a single oxidations for 1a-c. In addition, two reduction waves are observed for the bpy-Me ligands of 1a-c and 2a-c. All of the new compounds exhibit multiple metal-to-ligand charge transfer (MLCT) bands in the visible region of the spectrum. For compounds 1a-c the most intense absorption in the visible region decreases in energy as the length of the aromatic bridging ligands increases. By contrast the strongest absorption band of 2a is lower in energy than the most intense bands of both 2b and 2c. Single crystal X-ray analysis of 2a reveals that the bridging pyridine is coplanar with the pyridyl ring of the bpy-Me ligand that is attached to the Ru center. DFT calculations on 2a indicate that the HOMO is localized predominately on the {(NH₃)₅Ru-pyz-Ru(NH₃)₄} portion of the complex and the LUMO has slightly more contribution from the bpy-Me ligand.     

2-(1-(Dimethylamino)ethyl)phenylpalladium(II) complexes 5-functionalized with fluorous silyl tails

New fluorous-organometallics based on the chiral ligand α-methyl-N,N-dimethylbenzylamine (TMBA) were prepared by treatment of fluorous silyl bromide reagents with in situ 4-lithiated TMBA to give fluorous N,N-dimethyl(α-methyl-4-trialkylsilylbenzyl)amine ligands 1a-1c that vary in the number of fluorous tails attached to the Si atom. Ligands 1a-1c were successfully cyclo-palladated by treatment with Pd(OAc)₂/LiCl in methanol to furnish the corresponding chloride-bridged dimeric arylpalladium(II) complexes 2a-2c in good yields. The latter derivatives could be converted into monomeric Lewis-base adducts by complexation with pyridine (3a-3c), or triphenylphosphine (4a-4c). The crystal structure of triphenylphosphine complex 4a has been elucidated. To probe their fluorophilicity, the partition coefficient of each of the derivatives in the fluorous biphasic solvent (FBS) system perfluoromethylcyclohexane/n-octane has been determined.     

Synthesis and complexation of tetrakis(diphenylphosphinomethyl)calix[4]arene adopting the 1,3-alternate conformation

Novel upper-rim modified tetraphosphinocalix[4]arenes (5a-b) adopting 1,3-alternate conformation have been synthesized. Reaction of 5,11,17,23-tetrachloromethyl-25,26,27,28-tetrahydroxycalix[4]arene (1) with Ph₂POEt gave 5,11,17,23-tetrakis(diphenylphosphinoylmethyl)-25,26,27,28-tetrahydroxycalix[4]arene (2). Tetra-O-substitution of 2 with n-propyl iodide or benzyl bromide in the presence of K₂CO₃ carried out to afford 5,11,17,23-tetrakis(diphenylphosphinoylmethyl)-25,26,27,28-tetrapropoxy-(3a) or -benzyloxycalix[4]arene (3b), whereas di-O-substituted calix[4]arene, 5,11,17,23-tetrakis(diphenylphosphinoylmethyl)-25,27-dipropoxy-26,28-dihydroxycalix[4]arene (4), was obtained exclusively when Na₂CO₃ was used as base. Reduction of 3a-b with PhSiHCl₂ afforded 5,11,17,23-tetrakis(diphosphinomethyl)-25,26,27,28-tetrapropoxy-(5a) and -tetrabenzyloxycalix[4]arene (5b). ¹H and ¹³C NMR analysis reveals that the phosphines (5a-b) and the tetra-O-substituted phosphine oxides (3a-b) adopt 1,3-alternate conformation, while the parent tetrahydroxy-(2) and the di-O-propylated phosphine oxide (4) adopt cone-conformation. The X-ray structure indicates that the calix[4]arene moieties in 4 a pinched-cone conformation in solid state. Complexation of the phosphine ligand (5a) with [RuCl₂(p-cymene)]₂ affords the tetranuclear complexes, [{RuCl₂(p-cymene)}₂ · 5a] (6), as 1,3-alternate conformer.     

Diheteroarylmethyl substituted titanocenes: A novel class of possible anti-cancer drugs

From the reaction of tert-butyl lithium or n-butyl lithium with N-methylpyrrole (1a), furan (1b) or 2-bromo-thiophen (1c), 2-N-methylpyrrolyl lithium (2a), 2-furyl lithium (2b) or 2-thiophenyl lithium (2c), respectively, was obtained. When reacted with 6-(2-N-methylpyrrolyl) fulvene (3a), 6-(2-furyl) fulvene (3b) or 6-(2-thiophenyl) fulvene (3c), the corresponding lithiated intermediates were formed (4a-c). Titanocenes (5a-c) were obtained through transmetallation with titanium tetrachloride. When these titanocenes were tested against pig kidney epithelial (LLC-PK) cells, inhibitory concentrations (IC₅₀) of 32 μM, 140 μM, and 240 μM, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, compared to their ansa-analogues.     

Platinum(II) diphosphine complexes as catalysts for the Baeyer-Villiger oxidation of ketones: Is it possible to increase the concentration of the active species?

The synthesis and characterization of new bis-aquo platinum(II) complexes of the type [Pt(H₂O)(P-P)][OTf]₂ (OTf = triflate anion), in which the diphosphine P-P is a series of 1,n-bis-diphenyphosphinoalkanes (1a-d, with n = 1-4), 1,2-bis-(di-n-fluorophenylphosphino)ethanes (2a-c, with n = 2, 4-5) and 1,2-bis-dialkylphosphinoethanes (3a-e), where the alkyl substituents at phosphorus have been systematically changed (dmpe) (3a), (depe) (3b), (dippe) (3c), (dcype) (3d) are reported. These complexes were used as catalysts in the Baeyer-Villiger oxidation of 2-methylcyclohexanone, 2-methylcyclopentanone and cyclobutanone with 35% hydrogen peroxide as an environmentally friendly oxidant. The reactions were performed at 25 °C in a chlorinated solvent/H₂O two-phase system. All the investigated catalysts performed better than the corresponding dimeric complexes of general formula [Pt(μ-OH)(P-P)]₂[BF₄]₂ as a consequence of the positive effect imparted by the triflate counter-anion on catalysts speciation.     

Ring transformation and complex formation of 3-acetyl-4,5-dihydro-1,2,4-triazole oximes

Oximic 1,2,4-triazole ligands 2a-e were prepared from the reaction of 3-acetyl-4,5-dihydro-1H-1,2,4-triazoles 1a-e with hydroxylamine hydrochloride at room temperature. At higher temperatures, the reaction afforded, however, the novel ring transformation product 4-amino-2-(4-chlorophenyl)-5-methyl-2H-1,2,3,6-oxatriazine 3. The reaction of the ligands 2a-e with nickel (II) and palladium (II) acetates in ethanol at room temperature yielded the respective square planar complexes 5a-e, 6a,e. X-ray structure determination of one of these complexes (5a) revealed that metallation led to unexpected ring transformation of the triazole ligand. It is probable that such ring transformation generated the imidazole-N-oxide intermediate 4a which coordinated to Ni(II) ion, and the 4N-donor set comprises both imidazole nitrogen and arylhydrazone nitrogen. The whole process is associated with loss of one hydrogen molecule and formation of one new π-bond. The new compounds were characterized by elemental analysis, IR, ¹H NMR, ¹³C NMR and HRMS.     

Anticancer and antifungal activity of copper(II) complexes of quinolin-2(1H)-one-derived Schiff bases

The condensation of substituted aromatic aldehydes with 7-amino-4-methyl-quinolin-2(1H)-one (1) has lead to the isolation of quinolin-2(1H)-one derived Schiff bases (2-14). The copper(II) complexes (2a-14a) of the ligands were also prepared, and together with their corresponding free ligands were fully characterised by elemental analyses, spectral methods (IR, ¹H and ¹³C NMR, AAS, UV-Vis), magnetic and conductance measurements. The bidentate ligands coordinated to the copper(II) ion through the deprotonated phenolic oxygen and the azomethine nitrogen of the ligands in almost all cases. X-ray crystal structures of two of the complexes, 5a and 8a, confirmed the bidentate coordination mode. All of the compounds were investigated for their antimicrobial activities against the fungus, Candida albicans, and against Gram-positive and Gram-negative bacteria. The compounds were found to have excellent anti-Candida activity but were inactive against Staphylococcus aureus and Escherichia coli. Selected compounds (2-8 and 2a-8a) were also screened for their in vitro anticancer potential using the human hepatic carcinoma cell line, Hep-G₂. Several derivatives were shown to be active comparable to that of cisplatin.     

Platinum(II) and palladium(II) complexes with (N,N') and (C,N,N')- ligands derived from pyrazole as anticancer and antimalarial agents: synthesis, characterization and in vitro activities

The study of the reactivity of three 1-(2-dimethylaminoethyl)-1H-pyrazole derivatives of general formula [1-(CH₂)₂NMe₂}-3,5-R₂-pzol] {where pzol represents pyrazole and RH (1a), Me (1b) or Ph (1c)} with [MCl₂(DMSO)₂] (MPt or Pd) under different experimental conditions allowed us to isolate and characterize cis-[M{κ²-N,N′-{[1-(CH₂)₂NMe₂}-3,5-R₂-pzol])}Cl₂] {MMPtPt (2a-2c) or Pd (3a-3c)} and two cyclometallated complexes [M{κ³-C,N,N′-{[1-(CH₂)₂NMe₂}-3-(C₅H₄)-5-Ph-pzol])}Cl] {MPt(II) (4c) or Pd(II) (5c)}. Compounds 4c and 5c arise from the orthometallation of the 3-phenyl ring of ligand 1c. Complex 2a has been further characterized by X-ray crystallography. Ligands and complexes were evaluated for their in vitro antimalarial against Plasmodium falciparum and cytotoxic activities against lung (A549) and breast (MDA MB231 and MCF7) cancer cellular lines. Complexes 2a-2c and 5c exhibited only moderate antimalarial activities against two P. falciparum strains (3D7 and W2). Interestingly, cytotoxicity assays revealed that the platinacycle 4c exhibits a higher toxicity than cisplatin in the three human cell lines and that the complex 2a presents a remarkable cytotoxicity and selectivity in lung (IC₅₀ = 3 μM) versus breast cancer cell lines (IC₅₀ > 20 μM). Thus, complexes 2c and 4c appear to be promising leads, creating a novel family of anticancer agents. Electrophoretic DNA migration studies in presence of the synthesized compounds have been performed, in order to get further insights into their mechanism of action.     

Naphtho[2,3-d]isoxazole-4,9-dione-3-carboxylates: Potent, non-cytotoxic, antiapoptotic agents

Compounds containing a quinone moiety represent an important class of biologically active molecules that are widespread in nature, displaying anticancer, antibacterial, antimalarial, and fungicidal activities. In the course of designing 2,3-disubstituted-1,4-naphthoquinones derivatives as potential cysteine protease inhibitors, two naphtho[2,3-d]isoxazole-4,9-dione-3-carboxylates, 1a and 1b, were obtained. The antiapoptotic potential of 1a and 1b was then evaluated and compared to that of naphthoquinone 4. Primary rat hepatocytes were incubated with synthesized naphthoquinone derivatives and then exposed to the apoptotic stimulus camptothecin. Our results indicate that naphtho[2,3-d]isoxazole-4,9-dione-3-carboxylates 1a and 1b exerted a potent protective role in camptothecin-induced apoptosis in primary rat hepatocytes. Both 1a and 1b significantly increased cell viability, while reducing nuclear fragmentation, caspase-3, -8 and -9 activation, and cytochrome c release induced by camptothecin. In addition, 1a and 1b were shown to up-regulate Bcl-X_L, a pro-survival member of the Bcl-2 family of proteins, which modulates the mitochondrial pathway of apoptosis. Similar protective effects of quinone derivatives were seen in HuH-7 and PC12 cells incubated with distinct apoptotic stimuli, such as camptothecin, TGF-β1, or rotenone. Our results suggest that naphtho[2,3-d]isoxazole-4,9-dione-3-carboxylates 1a and 1b may act as potent, cytoprotective agents, through modulation of apoptotic pathways.     

Synthesis and antimicrobial activity of some new N-glycosides of 2-thioxo-4-thiazolidinone derivatives

5-Arylidene-2-thioxo-4-thiazolidinones 3a-f react with each of 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl and α-d-galactopyranosyl bromides 4a,b in acetone in the presence of aqueous potassium hydroxide at room temperature to afford N-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl) or N-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl) 2-thioxo-4-thiazolidinone derivatives 5a-f. Similarly, the reaction of 5-cycloalkylidene-2-thioxo-4-thiazolidinones 7a,b with 4a gave the corresponding N-glucosides 8a,b. Also, 5-pyrazolidene rhodanines 10a-e react with 4a to afford the new N-glucosides 11a-e. Treatment of compounds 15 and 16 with 4a in the presence of few drops of triethylamine or in KOH solution accomplished the mono- and bis-nucleosides 17 and 18, respectively. Some selected products were tested for their antimicrobial activities.